Col4a1 mutation in a mouse model of cerebral small vessel disease causes white matter defects that can be modulated...

Collagen IV, encoded by genes COL4A1/COL4A2, is a major component of the basement membrane, a specialised extracellular matrix (ECM) structure. Mutations in these genes cause a genetic form of cerebral small vessel disease (cSVD), a leading cause of stroke and dementia. White matter abnormalities are a hallmark of cSVD and are closely linked to cognitive decline and dementia. While white matter defects occur in patients with COL4A1/2 mutations, they remain understudied and their mechanisms are unclear. To address these knowledge gaps, we combined magnetic resonance diffusion tensor imaging, pathology, ultrastructural investigations, behaviour and proteomic analysis of white matter in an established mouse model of cSVD due to a Col4a1 mutation (Col4a1^+/Svc). The studies revealed that Col4a1^+/Svc mice have reduced myelinating oligodendrocyte pools, axonal myelination defects, and altered white matter structural integrity as well as cognitive impairments. Proteomic analysis of isolated white matter from Col4a1^+/Svc mice identified extensive changes to ECM and basement membrane composition. Furthermore, this provided evidence for altered endoplasmic reticulum (ER) biology including ER stress. To determine if white matter defects can be attenuated by targeting protein folding in the ER by promoting collagen IV secretion, we treated mice with the FDA-approved chemical chaperone 4-phenylbutyric acid. This revealed increased myelinating oligodendrocytes and improved axon-glial integrity in Col4a1^+/Svc mice. These data provide novel insight into the pathomolecular mechanisms of collagen IV mutations in white matter abnormalities in cSVD and identify a modifiable pathway as a putative therapeutic target.